The proposed research will compare global patterns of variation on the non-recombining portion of the Y chromosome (NRY), mitochondrial DNA (mtDNA), and the X chromosome in order to study the forces shaping human genome variation, and to test hypotheses about the history and demography of human populations. This research is motivated by the need to increase our knowledge of the history of our species and of the evolutionary forces predisposing certain populations to higher rates of genetic disease. The overall design will be to screen for nucleotide variation in 16 kilobases (kb) on the NRY, 3 kb of non-D- loop mtDNA, and 3 to 5 kb from each of two X chromosome loci (one low and one high recombination gene) in a sample of 550 chromosomes from 11 human populations, as well as a global sample of 50 males drawn from 26 worldwide populations. This nested sampling design will allow the direct comparison of two sampling strategies with different ascertainment biases, and will provide a sound framework for testing of a number of hypotheses pertaining to the demographic history and structure of human populations, different patterns of African versus non- African genetic variation, and male versus female migration rates. By analyzing loci with different mutation rates, recombination rates, and/or effective sizes, it should be feasible to disentangle the relative influences of locus-specific factors and a variety of population-level forces shaping human genome diversity. This research will also focus on regional-scale questions, with special emphasis on the genetic consequences of recent population dispersals. Specifically, it will develop the Jewish Diaspora as a model system, and will test hypotheses concerning the number and timing of founder events leading to increased frequencies of recessive diseases in Ashkenazi Jewish populations.